RESEARCH ARTICLE
Risk of Recurrence in Laryngeal Cancer Jesper Brandstorp-Boesen1,4*, Ragnhild Sørum Falk2, Jan Folkvard Evensen3, Morten Boysen1, Kjell Brøndbo1,4 1 Department of Otorhinolaryngology, Division of Surgery and Clinical Neuroscience, Oslo University Hospital, Oslo, Norway, 2 Oslo Centre for Biostatistics and Epidemiology, Research Support Service, Oslo University Hospital, Oslo, Norway, 3 Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway, 4 University of Oslo, Institute of Clinical Medicine, Oslo, Norway * [email protected]
Abstract
a11111
OPEN ACCESS Citation: Brandstorp-Boesen J, Sørum Falk R, Folkvard Evensen J, Boysen M, Brøndbo K (2016) Risk of Recurrence in Laryngeal Cancer. PLoS ONE 11(10): e0164068. doi:10.1371/journal. pone.0164068 Editor: Scott M. Langevin, University of Cincinnati College of Medicine, UNITED STATES Received: June 27, 2016 Accepted: September 19, 2016
A cohort study was undertaken to analyze the risk of recurrence among 1616 patients with primary squamous cell carcinoma of the larynx from 1983 to 2010 at a single, tertiary academic center in Oslo, Norway. The cohort was followed from the date of diagnosis to September 2011. Competing risk regression analysis assessed the association between various risk factors and the risk of recurrence, where death was considered a competing event. Recurrence was observed in 368 patients (23%) during the study period. The majority (71%) of recurrences involved the location of the primary tumor. The overall risk of recurrence during the first three years after initiating treatment was 20.5%. Increased risk of recurrence was observed in patients with supraglottic cancer, younger patients, those with T2–T3 tumors and in patients treated in the earlier part of the study period. Significant factors for recurrence in glottic carcinomas were age, treatment in the earlier part of the study and T-status, whereas age was a significant factor in supraglottic cancer. N-status appeared less significant. In conclusion, follow-up of laryngeal squamous cell carcinoma should place particular emphasis on the site of the primary tumor, younger patients, cases of supraglottic cancer and T2-T4 primary tumors, especially during the first three years after treatment. More studies are needed to assess the impact of surgical versus non-surgical treatment, and eventually the significance of recurrence, for disease-specific and overall survival in cases of advanced laryngeal squamous cell carcinoma.
Published: October 7, 2016 Copyright: © 2016 Brandstorp-Boesen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper. Funding: The study received no external support or funding. Competing Interests: The authors have declared that no competing interests exist.
Introduction Laryngeal squamous cell carcinoma (LSCC) accounts for approximately 17% of all primary head and neck cancers (HNSCC) in Norway, with an age-standardized incidence rate (ASR) for laryngeal cancer of 1.4 per 100,000 in 2014 [1]. Males with glottic cancer predominate, but during the last three decades the proportion of females has increased significantly [2]. The treatment of early and advanced stage laryngeal cancer has been subject to a substantial development during the last three decades. The objective of LSCC management is cure with preserved laryngeal function. To achieve this, it is vital to assess the risk of recurrent disease in each case. The risk of recurrence varies considerably with the modality of treatment, as with subsite, N-status and T-status [3, 4]. Early stage laryngeal cancer is generally associated with
PLOS ONE | DOI:10.1371/journal.pone.0164068 October 7, 2016
1 / 15
Risk of Recurrence in Laryngeal Cancer
high local control rates and a favorable outcome [5]. However the recurrence rates of advanced stage LSCC have been reported to range between 25–50% [6]. Moreover, previous studies have shown that laryngeal recurrences primarily develop in the region of the primary tumor and within three years after the primary therapy [7]. Early detection of recurrent disease in LSCC is an important contributor to a successful disease outcome [8]. Thus, identification of prognostic factors for recurrence would be highly relevant to the clinician. The objective of this study was to analyze the subsite-specific risk factors for recurrence in patients treated for LSCC.
Materials and Methods All patients diagnosed with primary LSCC at the Department of Otorhinolaryngology, Oslo University Hospital, Rikshospitalet during 1983–2010 were included in the study. The Privacy and Data Protection Office, CEO Executive Staff, Oslo University Hospital approved the study and data collection was authorized by the Norwegian Data Protection Authority. Written consent was collected from each patient at the time of diagnosis. Baseline data on gender, smoking/alcohol status, age, subsite and TNM status at diagnosis as well as date of diagnosis, date of primary treatment, modality of treatment and follow-up were obtained from the hospital records and compiled in a database. Information about deaths (or date of emigration) was obtained from the hospital patient registration system, which is updated regularly from the Cause of Death Registry. The data were linked through unique personal identification numbers, which are assigned to every individual in Norway. Longitudinal follow-up of the cohort was continued until 30 September 2011. The Ministry of Health approved the study and data collection was authorized by the Norwegian Data Inspectorate. After clinical and radiological examination, all patients were evaluated by a multidisciplinary tumor board of head and neck surgeons and oncologists from the Norwegian Radium Hospital. The final management was performed in accordance with the Danish Head and Neck Cancer Group (DAHANCA) guidelines, which have been applied since 1995 [9]. Between 1983–1995, T1AN0M0 glottic carcinomas were treated with conventional RT (66 Gy, 2 Gy per fraction, 5 fractions/week), but since 1 January 1996, TLM has been the standard treatment for these tumors. From 1983, early and intermediate stage laryngeal cancer was managed by a conventional RT scheme (68–70 Gy, 5 fractions/week) but during1995–2000 an accelerated protocol (6 fractions/ week) was gradually introduced according to DAHANCA guidelines [10]. Concomitant CRT was introduced as standard treatment for advanced stages in 2002, whereas T4a laryngeal cancers continued to be treated with TLAR and post-operative RT (50 Gy). Partial laryngectomy is not part of standard treatment at our center and has only been performed in a few selected cases. Regardless of stage and treatment modality, all patients were evaluated clinically 4–6 weeks after primary treatment. Before 1990, endoscopy was performed with a mirror or Hopkins rod and after 1990 by means of flexible videolaryngoscopy, supplemented with stroboscopy as appropriate. A computed tomographic (CT) scan of the neck was performed before the first consultation for all patients (except T1a glottic cancer treated by TLM) and was repeated annually and/or when required for a complete assessment. Initially, conventional chest x-ray was performed regularly but was stopped halfway through the study due to the low detection rate for metastases and secondary malignant tumors. Ultrasound examination of the neck with fine-needle cytology and/or micro-laryngoscopy with a biopsy was performed when required. Patients were seen every 8–12 weeks during the first year and 2–3 times during the second and third years post-treatment. Thereafter the surveillance was continued by the local Ear, Nose and Throat Department in the majority of cases. Any suspicion of recurrence during follow-up led to immediate referral to our institution for further examination and treatment.
PLOS ONE | DOI:10.1371/journal.pone.0164068 October 7, 2016
2 / 15
Risk of Recurrence in Laryngeal Cancer
As per the department protocol, first follow-up consultations were carried out by the senior staff member, who was responsible for the initial TNM classification and the primary treatment decision. Our database is updated continuously regarding the site of recurrence and occurrence of death. The date of recurrence was defined at the date of histological verification. Recurrences were categorized as local, regional, loco-regional or metastases at distant sites. In case of simultaneous recurrence in more than one site, both sites were registered. Recurrence in the stoma in patients subjected to primary total laryngectomy was defined as local-stoma. The cohort was categorized by gender, smoking/alcohol (ever, never, unknown), age (59, 60–69 and 70 years), subsite (glottic, supraglottic or subglottic) and stage of disease. All tumors were classified in accordance with the UICC TNM staging system and the AJCC TNM (stage I–IV), where early stage (I+II) is defined as T1-T2N0M0, and advanced stage (III+IV) is defined as T3–T4a/b and any TN+, M+. The cohort was divided into four time periods according to the year of initial management (1983–1989, 1990–1996, 1997–2003, 2004–2010) and categorized by one of the treatment modalities: RT, TLM, TLAR, CRT or palliative/no treatment.
Statistics Descriptive statistics are presented as frequencies and proportions. The cohort was followed up longitudinally from the date of primary diagnosis, whereas the date of initiated treatment was applied as start point in the risk analysis. Due to the possibility of death during the follow-up period, death as a competing event was incorporated into the analysis. Thus, the patients were followed to the date of histologically verified recurrence or censored at the date of study closure (30 September 2011), or considered as a competing event at the time of death (from any cause), whichever occurred first. The cumulative risk of recurrence, which describes the absolute risk over the time course, was plotted during 10 years of follow-up and is presented as risk estimates at three years after treatment of LSCC. The Pepe and Mori test was performed to compare the cumulative risk of glottic versus supraglottic cancer [11]. Univariate and multivariate competing risk analyses, using the model of Fine and Gray [12], were performed to evaluate the effect of potential risk factors for recurrence during 10 years of follow-up after treatment of LSCC. Stage could not be included in the model due to high correlation with T- and N-status. Smoking/alcohol was omitted from the multivariate model due to lack of detailed data on consumption. Risk estimates are presented as sub-distribution hazard ratios (SHR) with accompanying 95% confidence intervals (CI) and p values. The analyses are stratified by subsite to meet the model assumptions of proportional hazards. Only glottic and supraglottic carcinomas had a sufficient number of patients for analysis. Sensitivity analyses were conducted by restricting the follow-up to three years after initiation of treatment, due to the low number of cases followed beyond three years (11%). P-values 0.05 were regarded as statistically significant. Data analysis was performed using SPSS [13] and Stata [14].
Results In total, 1616 patients were diagnosed with primary LSCC during the study period. One patient was excluded since he died on the day of diagnosis, such that 1615 patients were included in the analysis. The long-term descriptive trends of the study cohort have been published previously [2]. Among these 1615 cases, 368 (23%) patients developed recurrent disease. Death as a competing event occurred in 674 (42%) patients. The median follow-up time for the whole cohort was 3.2 years (range 0–28.3 years). Patients with and without recurrent disease had a median follow-up of 1.0 years and 5.2 years, respectively. Ninety-eight percent of patients (n = 1583)
PLOS ONE | DOI:10.1371/journal.pone.0164068 October 7, 2016
3 / 15
Risk of Recurrence in Laryngeal Cancer
were treated with curative intent, while 2% (n = 32) were considered medically or mentally unfit for curative treatment or the patients abstained from treatment. Patient and disease characteristics are summarized in Table 1. In the first period (1983–89) the risk of recurrence was 28% (113/402), after which the risk declined gradually to 17% (73/ 434) in the last period (2004–10). The cumulative risk of recurrence for the whole cohort at 1, 3, 5 and 10 years of follow-up was 11.3%, 20.5%, 22.5% and 23.6%, respectively, while the risk of death increased steadily over time (Fig 1). The risk of recurrence tended to be more striking in supraglottic versus glottic carcinomas over the 10 years following treatment, although this was not statistically significant (p = 0.09, Fig 2).The three-year risk of recurrence decreased by age at diagnosis and period of treatment (Table 2). Furthermore, the three-year risk was lowest for T1 (11%) and T4 (21.1%) laryngeal cancer, while T2 (27.3%) and particularly T3 (35.8%) laryngeal cancer were associated with higher risks for recurrence. The risk of recurrence increased with increasing nodal involvement and stage (early versus advanced) (Table 2). Among patients with T1a glottic cancer, the risk of recurrence was similar in patients treated with RT (three-year cumulative risk 8.7%, 95%CI 5.6–12.7%) or TLM (8.7%, 5.9–12.3%). When a competing risk regression model was used to study the association between potential factors and the risk of recurrence in glottic cancer (Table 3), the risk decreased significantly for patients treated in the last period compared to the first period (SHR 0.5, 95% CI 0.3–0.8). The risk of recurrence was significantly lower for patients aged 70 years compared to
Risk of Recurrence in Laryngeal Cancer Jesper Brandstorp-Boesen1,4*, Ragnhild Sørum Falk2, Jan Folkvard Evensen3, Morten Boysen1, Kjell Brøndbo1,4 1 Department of Otorhinolaryngology, Division of Surgery and Clinical Neuroscience, Oslo University Hospital, Oslo, Norway, 2 Oslo Centre for Biostatistics and Epidemiology, Research Support Service, Oslo University Hospital, Oslo, Norway, 3 Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway, 4 University of Oslo, Institute of Clinical Medicine, Oslo, Norway * [email protected]
Abstract
a11111
OPEN ACCESS Citation: Brandstorp-Boesen J, Sørum Falk R, Folkvard Evensen J, Boysen M, Brøndbo K (2016) Risk of Recurrence in Laryngeal Cancer. PLoS ONE 11(10): e0164068. doi:10.1371/journal. pone.0164068 Editor: Scott M. Langevin, University of Cincinnati College of Medicine, UNITED STATES Received: June 27, 2016 Accepted: September 19, 2016
A cohort study was undertaken to analyze the risk of recurrence among 1616 patients with primary squamous cell carcinoma of the larynx from 1983 to 2010 at a single, tertiary academic center in Oslo, Norway. The cohort was followed from the date of diagnosis to September 2011. Competing risk regression analysis assessed the association between various risk factors and the risk of recurrence, where death was considered a competing event. Recurrence was observed in 368 patients (23%) during the study period. The majority (71%) of recurrences involved the location of the primary tumor. The overall risk of recurrence during the first three years after initiating treatment was 20.5%. Increased risk of recurrence was observed in patients with supraglottic cancer, younger patients, those with T2–T3 tumors and in patients treated in the earlier part of the study period. Significant factors for recurrence in glottic carcinomas were age, treatment in the earlier part of the study and T-status, whereas age was a significant factor in supraglottic cancer. N-status appeared less significant. In conclusion, follow-up of laryngeal squamous cell carcinoma should place particular emphasis on the site of the primary tumor, younger patients, cases of supraglottic cancer and T2-T4 primary tumors, especially during the first three years after treatment. More studies are needed to assess the impact of surgical versus non-surgical treatment, and eventually the significance of recurrence, for disease-specific and overall survival in cases of advanced laryngeal squamous cell carcinoma.
Published: October 7, 2016 Copyright: © 2016 Brandstorp-Boesen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper. Funding: The study received no external support or funding. Competing Interests: The authors have declared that no competing interests exist.
Introduction Laryngeal squamous cell carcinoma (LSCC) accounts for approximately 17% of all primary head and neck cancers (HNSCC) in Norway, with an age-standardized incidence rate (ASR) for laryngeal cancer of 1.4 per 100,000 in 2014 [1]. Males with glottic cancer predominate, but during the last three decades the proportion of females has increased significantly [2]. The treatment of early and advanced stage laryngeal cancer has been subject to a substantial development during the last three decades. The objective of LSCC management is cure with preserved laryngeal function. To achieve this, it is vital to assess the risk of recurrent disease in each case. The risk of recurrence varies considerably with the modality of treatment, as with subsite, N-status and T-status [3, 4]. Early stage laryngeal cancer is generally associated with
PLOS ONE | DOI:10.1371/journal.pone.0164068 October 7, 2016
1 / 15
Risk of Recurrence in Laryngeal Cancer
high local control rates and a favorable outcome [5]. However the recurrence rates of advanced stage LSCC have been reported to range between 25–50% [6]. Moreover, previous studies have shown that laryngeal recurrences primarily develop in the region of the primary tumor and within three years after the primary therapy [7]. Early detection of recurrent disease in LSCC is an important contributor to a successful disease outcome [8]. Thus, identification of prognostic factors for recurrence would be highly relevant to the clinician. The objective of this study was to analyze the subsite-specific risk factors for recurrence in patients treated for LSCC.
Materials and Methods All patients diagnosed with primary LSCC at the Department of Otorhinolaryngology, Oslo University Hospital, Rikshospitalet during 1983–2010 were included in the study. The Privacy and Data Protection Office, CEO Executive Staff, Oslo University Hospital approved the study and data collection was authorized by the Norwegian Data Protection Authority. Written consent was collected from each patient at the time of diagnosis. Baseline data on gender, smoking/alcohol status, age, subsite and TNM status at diagnosis as well as date of diagnosis, date of primary treatment, modality of treatment and follow-up were obtained from the hospital records and compiled in a database. Information about deaths (or date of emigration) was obtained from the hospital patient registration system, which is updated regularly from the Cause of Death Registry. The data were linked through unique personal identification numbers, which are assigned to every individual in Norway. Longitudinal follow-up of the cohort was continued until 30 September 2011. The Ministry of Health approved the study and data collection was authorized by the Norwegian Data Inspectorate. After clinical and radiological examination, all patients were evaluated by a multidisciplinary tumor board of head and neck surgeons and oncologists from the Norwegian Radium Hospital. The final management was performed in accordance with the Danish Head and Neck Cancer Group (DAHANCA) guidelines, which have been applied since 1995 [9]. Between 1983–1995, T1AN0M0 glottic carcinomas were treated with conventional RT (66 Gy, 2 Gy per fraction, 5 fractions/week), but since 1 January 1996, TLM has been the standard treatment for these tumors. From 1983, early and intermediate stage laryngeal cancer was managed by a conventional RT scheme (68–70 Gy, 5 fractions/week) but during1995–2000 an accelerated protocol (6 fractions/ week) was gradually introduced according to DAHANCA guidelines [10]. Concomitant CRT was introduced as standard treatment for advanced stages in 2002, whereas T4a laryngeal cancers continued to be treated with TLAR and post-operative RT (50 Gy). Partial laryngectomy is not part of standard treatment at our center and has only been performed in a few selected cases. Regardless of stage and treatment modality, all patients were evaluated clinically 4–6 weeks after primary treatment. Before 1990, endoscopy was performed with a mirror or Hopkins rod and after 1990 by means of flexible videolaryngoscopy, supplemented with stroboscopy as appropriate. A computed tomographic (CT) scan of the neck was performed before the first consultation for all patients (except T1a glottic cancer treated by TLM) and was repeated annually and/or when required for a complete assessment. Initially, conventional chest x-ray was performed regularly but was stopped halfway through the study due to the low detection rate for metastases and secondary malignant tumors. Ultrasound examination of the neck with fine-needle cytology and/or micro-laryngoscopy with a biopsy was performed when required. Patients were seen every 8–12 weeks during the first year and 2–3 times during the second and third years post-treatment. Thereafter the surveillance was continued by the local Ear, Nose and Throat Department in the majority of cases. Any suspicion of recurrence during follow-up led to immediate referral to our institution for further examination and treatment.
PLOS ONE | DOI:10.1371/journal.pone.0164068 October 7, 2016
2 / 15
Risk of Recurrence in Laryngeal Cancer
As per the department protocol, first follow-up consultations were carried out by the senior staff member, who was responsible for the initial TNM classification and the primary treatment decision. Our database is updated continuously regarding the site of recurrence and occurrence of death. The date of recurrence was defined at the date of histological verification. Recurrences were categorized as local, regional, loco-regional or metastases at distant sites. In case of simultaneous recurrence in more than one site, both sites were registered. Recurrence in the stoma in patients subjected to primary total laryngectomy was defined as local-stoma. The cohort was categorized by gender, smoking/alcohol (ever, never, unknown), age (59, 60–69 and 70 years), subsite (glottic, supraglottic or subglottic) and stage of disease. All tumors were classified in accordance with the UICC TNM staging system and the AJCC TNM (stage I–IV), where early stage (I+II) is defined as T1-T2N0M0, and advanced stage (III+IV) is defined as T3–T4a/b and any TN+, M+. The cohort was divided into four time periods according to the year of initial management (1983–1989, 1990–1996, 1997–2003, 2004–2010) and categorized by one of the treatment modalities: RT, TLM, TLAR, CRT or palliative/no treatment.
Statistics Descriptive statistics are presented as frequencies and proportions. The cohort was followed up longitudinally from the date of primary diagnosis, whereas the date of initiated treatment was applied as start point in the risk analysis. Due to the possibility of death during the follow-up period, death as a competing event was incorporated into the analysis. Thus, the patients were followed to the date of histologically verified recurrence or censored at the date of study closure (30 September 2011), or considered as a competing event at the time of death (from any cause), whichever occurred first. The cumulative risk of recurrence, which describes the absolute risk over the time course, was plotted during 10 years of follow-up and is presented as risk estimates at three years after treatment of LSCC. The Pepe and Mori test was performed to compare the cumulative risk of glottic versus supraglottic cancer [11]. Univariate and multivariate competing risk analyses, using the model of Fine and Gray [12], were performed to evaluate the effect of potential risk factors for recurrence during 10 years of follow-up after treatment of LSCC. Stage could not be included in the model due to high correlation with T- and N-status. Smoking/alcohol was omitted from the multivariate model due to lack of detailed data on consumption. Risk estimates are presented as sub-distribution hazard ratios (SHR) with accompanying 95% confidence intervals (CI) and p values. The analyses are stratified by subsite to meet the model assumptions of proportional hazards. Only glottic and supraglottic carcinomas had a sufficient number of patients for analysis. Sensitivity analyses were conducted by restricting the follow-up to three years after initiation of treatment, due to the low number of cases followed beyond three years (11%). P-values 0.05 were regarded as statistically significant. Data analysis was performed using SPSS [13] and Stata [14].
Results In total, 1616 patients were diagnosed with primary LSCC during the study period. One patient was excluded since he died on the day of diagnosis, such that 1615 patients were included in the analysis. The long-term descriptive trends of the study cohort have been published previously [2]. Among these 1615 cases, 368 (23%) patients developed recurrent disease. Death as a competing event occurred in 674 (42%) patients. The median follow-up time for the whole cohort was 3.2 years (range 0–28.3 years). Patients with and without recurrent disease had a median follow-up of 1.0 years and 5.2 years, respectively. Ninety-eight percent of patients (n = 1583)
PLOS ONE | DOI:10.1371/journal.pone.0164068 October 7, 2016
3 / 15
Risk of Recurrence in Laryngeal Cancer
were treated with curative intent, while 2% (n = 32) were considered medically or mentally unfit for curative treatment or the patients abstained from treatment. Patient and disease characteristics are summarized in Table 1. In the first period (1983–89) the risk of recurrence was 28% (113/402), after which the risk declined gradually to 17% (73/ 434) in the last period (2004–10). The cumulative risk of recurrence for the whole cohort at 1, 3, 5 and 10 years of follow-up was 11.3%, 20.5%, 22.5% and 23.6%, respectively, while the risk of death increased steadily over time (Fig 1). The risk of recurrence tended to be more striking in supraglottic versus glottic carcinomas over the 10 years following treatment, although this was not statistically significant (p = 0.09, Fig 2).The three-year risk of recurrence decreased by age at diagnosis and period of treatment (Table 2). Furthermore, the three-year risk was lowest for T1 (11%) and T4 (21.1%) laryngeal cancer, while T2 (27.3%) and particularly T3 (35.8%) laryngeal cancer were associated with higher risks for recurrence. The risk of recurrence increased with increasing nodal involvement and stage (early versus advanced) (Table 2). Among patients with T1a glottic cancer, the risk of recurrence was similar in patients treated with RT (three-year cumulative risk 8.7%, 95%CI 5.6–12.7%) or TLM (8.7%, 5.9–12.3%). When a competing risk regression model was used to study the association between potential factors and the risk of recurrence in glottic cancer (Table 3), the risk decreased significantly for patients treated in the last period compared to the first period (SHR 0.5, 95% CI 0.3–0.8). The risk of recurrence was significantly lower for patients aged 70 years compared to
